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For personal use only. 1995 85: 3746-3753 Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study RA Nash, R Etzioni, R Storb, T Furlong, T Gooley, C Anasetti, FR Appelbaum, K Doney, P Martin and J Slattery Updated information and services can be found at: http://www.bloodjournal.org/content/85/12/3746.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. From www.bloodjournal.org by guest on November 7, 2014. For personal use only. Tacrolimus (FK506) Alone or in Combination With Methotrexate or Methylprednisolone for the Prevention of Acute Graft-Versus-Host Disease After Marrow Transplantation From HLA-Matched Siblings: A Single-Center Study By Richard A. Nash, Ruth Etzioni, Rainer Storb, Terry Furlong, Ted Gooley, Claudio Anasetti, Frederick R. Appelbaum, Kristine Doney, Paul Martin, John Slattery, Keith Sullivan, Richard van der Jagt, Robert Witherspoon, William J. Jusko, Richard A. Zager, and H. Joachim Deeg The pharmacokinetics, safety, and efficacy in marrow transplantation of FK506-basedimmunosuppression forgraft-versus-host disease (GVHD) prophylaxis was evaluated in an open label pilot study of 18 patients. Patients more than12 years of age (median, 35 years; range, 15 t o 50 years) with advanced hematologic malignancies receiving HLA-matched sibling marrow grafts were randomized t o receive FK506 alone, FK506and methotrexate(MTX), or FK506 and methylprednisolone. Of 17 evaluable patients, all had evidence of sustained marrow engraftment. The median time to an absolute neutrophil count of greater than 500/pL was 15 days for patientsreceiving FK506 alone or FK506 plus methylprednisolone and 23 days for FK506 plus shortMTX. Pharmacokinetic studiesdid not showany significant difference in clearance of FK506 when administered alone or in combination with methylprednisolone or MTX. The mean bioavailability after oral administration in these same three groups was 0.49 f 0.1,0.27 f 0.12, and 0.16 f 0.08, respectively (P= ,003).The decrease in bioavailability may have resulted from an exacerbation ofradiation-inducedgastroenteritis by MTX. The most significant adverse effect associated with the administration of FK506 was nephrotoxicity, which occurred in 14 of 18 patients (78%). The mean glomerular filtration rate, determined by clearance of (g9v~)DTPA,decreased t o 5640 (?18%) of the pretransplant baseline level by week 8 (P= .002). Eight of 18 patients (44'70) developed grades Il-IV acute GVHD, predominantly of the skin and gastrointestinal tract. The actuarial probability of transplantrelated mortality during the first 100 days was 2490. The actuarial probability of l-year disease-free survival was3990. In conclusion, although bioavailability of FK506 may be affected in patients receiving MTX, this study suggests that FK506 may have a role in the management of patients after allogeneic marrow transplantation. 0 7995 by The American Society of Hematology. A of acute GVHD andmay avoid thetoxicities associated with previously established regimens. The macrolide FK506 produced by Streptomyces tsukubaensis inhibits T-cell activation by forming a complex with the FK binding protein- 12 that blocks the serine-threonine phosphatase activity of calcineurin." This prevents interleukin-2 (IL-2) transcription mediated by NF-AT on the 1L-2 gene promoter. FK506 inhibits certain pathways of T-cell activationsuchasthosemediated by theT-cell receptor CD3complexand by CD2 but did notaffectthe T-cell proliferation induced by CD28-specific monoclonal antibodies in the presence ofphorbol12-myristate 13-acetate."." Clinical studies with FK506 were first performed in liver transplantation. In this setting, FK506 is effective forprevention of graft rejection and has also been effective as salvage therapy to control episodes of graft rejection.""' Preclinical studies of FK506 after marrow transplantation in arat model that was fully major histocompatibility complex (MHC) and non-MHC disparate showed that GVHD could be prevented or treated s u c ~ e s s f u l l y . ' ~In. ' ~a model established to study GVHD, dogswere grafted with unrelated MHC-nonidentical marrow after 920 cGy total body irradiation (TBI)." In the group of dogs thatreceived FK506 incombinationwith MTX, survival was prolonged when compared with controls receiving no immunosuppression or FK506 alone. Based on thesestudies of immunosuppressive activity and because there werenopreviousreports of the use of FK506 with MTX or prednisone for acute GVHD prophylaxis,a pilot study was conducted in patients with advanced hematologic malignancies to investigate drug interactions and safety. CUTE GRAR-VERSUS-HOST disease (GVHD) contributessignificantly tothe morbidity and mortality associated with allogeneic marrow transplantation.',* Previous studies have shown that the combination of cyclosporine (CSP) and four dosesof methotrexate (MTX) is moreeffective than either agent alone in prevention of acute GVHD.',4 Prednisone is an effective agent fortherapy of acute GVHD and has been studied in combination with CSP for prophylaxis.5-8 In more recentstudies, the combination of CSP, MTX, and prednisone was more effective in preventing acute GVHD than the combination of CSP and prednisone, but was not more effective than the combination of CSP and MTX.9.'0 Although the combination of immunosuppressive agents has reduced the incidence of GVHD, the use of new agents (possibly in combination with MTX and prednisone) may permit a further reduction in the incidence or severity From the Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, WA; and the School of Pharmacy, State University of New York at Buffalo, NY. Submitted October 14, 1994: accepted January 21, 1995. Supported in part by Grants No. CA-18029, CA-18221, CA-15704, GM-24211, and HL-36444 awarded by the National Institutes oj Health, Department of Health and Human Services; and b.y Fujisawa USA, Inc, Deetjield, IL. Address reprint requests to Richard A. Nush, MD, Fred Hutchinson Cancer Research Center, 1124 Columbia St. M318, Seattle. WA 98/04-2092, The publicationcosts of this article were defrayed in purl by page charge payment. This article must therefre be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact. 0 1995 by The American Society of Hematology. 0006-4971/95/8512-0006$3.00/0 3746 MATERIALS AND METHODS Patients. From July 1992 to August 1993, 18 patients were registered on this protocol. Patient characteristics are shown in Table 1 . Blood, Vol 85, No 12 (June 15). 1995: pp 3746-3753 From www.bloodjournal.org by guest on November 7, 2014. For personal use only. PREVENTIONOF 3747 GVHD AFTER BMT WITHFK506 Table 1. Patient Characteristics n 1%) Age (yr) <35 >35 9 (50) 9 (50) Diagnosis Acute leukemia-relapse Acute leukemia-remission 6 (33) 1 (6) 2 (11) 8 (44) 1 (6) MDS Malignant lymphoma in relapse CML-blast crisis Conditioning regimen Cy/TBl (1,575 cGy) Bu/Cy/TBI (1.200 cGy) 11 (61) 6 (33) 1 (6) BCV Patient sex Male Female Donor parity-sedpatient sex Nonparous femaleflemale Parous female/female Male/female Nonparous female/male Parous female/male Male/male ~~~~~ 14 (78) 4 (22) 0 0 4 (22) 1 (6) 5 (28) 8 (44) ~ ~ The protocol and consent forms were approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center. The risks and benefits of the treatment regimens were explained to each patient in detail before hospital admission. Patients were sequentially randomized to one ofthe three regimens of GVHD prophylaxis: m506 alone, FK506 and MTX, or K 5 0 6 and methylprednisolone. In this small group of patients, a randomized selection of patients to each GVHD prophylaxis group allowed a comparison of the pharmacokinetic data. Conditioning regimens. Before marrow transplantation, patients with lymphoid malignancies (acute leukemia or lymphoma) received intravenous cyclophosphamide (60 mgkg body weight) on each of 2 successive days followed by 2.25 Gy to TB1 on each of 7 successive days (1,575 cGy). Patients with myeloid malignancies (acute leukemia, chronic myeloid leukemia [CML] in blast crisis, or myelodysplasia) received oral busulfan (7 mgkg over 4 days) and cyclophosphamide (50 mgkg/day over 2 days), followed by 200 cGy of TB1 on each of 6 successive days (1,200 cGy). One patient received a chemotherapy regimen consisting of BCNU, cyclophosphamide, and VP-16 because of a past history of radiation to the mediastinum. The radiation was delivered by two opposing “CO sources at a rate of 6.5 cGy/min. Within 4 hours of the last dose of TB1 or 36 hours after the last dose of cyclophosphamide, donor marrow was infused intravenously. The day of marrow infusion was designated as day 0. Engraftment was defined as thefirst day a neutrophil count was greater than 500 X lO‘L and was sustained for 2 days. Eight patients with lymphoid malignancies were treated with recombinant a-interferon (IFN) when neutrophil counts were sustained greater than 200 X 106Lfor 3 days as part of an investigational protocol evaluating theriskof relapse after marrow transplantation. GVHDprophylmis, assessment, and treatment. Postgrafting immunosuppression in all study patients included FK506 alone or in combination with methylprednisolone or MTX. FK506 was begun on the day before marrow infusion. In this pilot study, the intravenous dose was 0.03 mgkg/d as a continuous intravenous infusion, which wasmaintained until the patients had recovered from regimen- related gastrointestinal toxicity, when oral FK506 (0.15 mgkg/d in 2 divided doses) was substituted. After the seventh patient on study, the oral dose was reduced to 0.12 mgkgld. The MTX dose was 15 mg/mz on day 1 and then 10 mg/m2 on days 3, 6, and I 1 after marrow transplantation. Methylprednisolone was started at 0.5 mg/ kg on day 7 and was increased to 1 mgkg from day 15 through day 28 and then tapered through day 72.’.” The full dose of FK506 was administered until day 60 unless adverse effects or acute GVHD developed. Generally, if the serum creatinine doubled above baseline values or increased above 2 mg/dL, the FK506 dose was reduced or temporarily withheld. After day 60, if the patients had no evidence of GVHD, the FK506 dose was tapered until the drug was discontinued by day 180. If patients relapsed, FK506 was stopped. FK506 steady-state levels during continuous intravenous infusion or trough levels during oral treatment were determined by enzyme-linked immunosorbent assay (ELISA).21.22 An attempt was made to maintain FK506 whole blood levels between 2 and 60 ng/mL. Donors and recipients were genotypically HLA-identical as determined by serologic histocompatibility typing for HLA-A and B and the results of HLA-DRB1 DNA analysis based on allelic typing by polymerase chain reaction (PCR)/sequence-specific oligonucleotide probe hybridization (SSOP).z3.24 Assessment, grading, and treatment of acute GVHD have been previously reported? The time period after stopping FK506 was not evaluated for GVHD if patients had relapsed or elected to withdraw from the study with no GVHD or FK506-related toxicity. Acute GVHD was treated with methylprednisolone at 2 mgkg/d for at least 14 days andthentapered over 8 weeks if tolerated. Alternatively, patients were enrolled inan investigational protocol with oral nonabsorbable beclomethasone if GVHD was isolated to the upper gastrointestinal tract. Before discharge home, patients were evaluated for chronic GVHD.25-27 Treatment of cGVHD was with FK506 0.12 mgkg/d in two doses 12 hours apart and every other day with prednisone at 1 mgkg. This regimen is similar to that previously reported with CSP except that FK506 was administered daily instead of every other day.” Pharmacokinetics. Whole blood levels of FK506 were determined by a previously described ELISA.Z1~?2 Plasma methylprednisolone and cortisol were measured using the high performance liquid chromatography (HPLC) method of Ebling et al.?’ Plasma prednisone, prednisolone, and cortisol were measured using the modified HPLC method ofRose and J u s ~ o . Least-squares ’~ regression calculations related to standard curves were performed using the variance stabilizing transformation method.” The area under the curve (AUC) for individual corticosteroid profiles from zero to infinity was calculated using a spline computer program. In 17 patients, serial blood samples were obtained during continuous intravenous infusion of FK506 on day 1 1 after the administration of MTX and methylprednisolone for determination of the clearance of FK506 and methylprednisolone pharmacokinetics. Whole blood samples were drawn before the morning dose of MTX or methylprednisolone and then at 0.5, 1, 2, 4, 6, 8, and 12 hours after MTX or methylprednisolone dosing. In the group of patients who received neither MTXnor methylprednisolone, whole blood samples were drawn at similar time points in the morning to make them comparable. In 14 patients, a 12-hour pharmacokinetic profile of FK506 was obtained between weeks 4 and 8 after oral administration of a constant dose for 4 consecutive days. Whole blood samples (3 mL) were drawn before the morning dose of FK506 and at 0.5, I , 1.5. 2,3,4,6,8, and 12 hours after the dose. These data and the clearance of FK506 calculated from the pharmacokinetic profile obtained on day 1 1 were used to assess bioavailability. MTX concentrations were measured only at 24 hours after the dose. If the 24-hour MTX level was greater than 0.04 bmol/L, rescue with Leucovorin was started. Assessment of renalfunction and toxicities. To assess the effects on renal function, the glomerular filtration rate (GFR) was deter- From www.bloodjournal.org by guest on November 7, 2014. For personal use only. 3748 NASH ET AL mined before and during week 8 after marrow transplantation. The GFR was determined by clearance of technetium-99m (w"Tc)-diethylenetriamine-pentaacetic acid (DTPA) from protein-free ultrafiltered plasma. The DTPAwas injected andblood levels ofDTPA measured at I hour. The GFR was calculated from this result."' Nephrotoxicity was defined as a doubling of serum creatinine greater than baseline or a serum creatinine greater than 2 mg/dL. This degree of renal dysfunction was defined as significant because doses of nephrotoxic agents such as FK506 were adjusted at this point. Veno-occlusive disease (VOD) has been previously described and defined.32 Hypertension was defined as a diastolic blood pressure greaterthan 90 mm Hg or a systolic blood pressure greater than 140 mm Hg sustained for more than 3 consecutive days and requiringtreatment.Hyperglycemiawas defined as a serum glucose level greater than 140 mgldL and requiring treatment.Hyperlipidemiawas defined asa serum total cholesterol concentration 2240 mgldL. Srurisrics. Cumulative incidence curves and corresponding statistical tests were used to describe acute GVHD and nephrotoxicit^.''.^^ Kaplan Meier curves were used to describe transplant-related mortality and disease-free survival. The Wilcoxon signed rank test for matched pairs was used to compare GFR values before and after transplant. An analysis of variance was used to compare bioavailability and clearance of FK506 among the three different groups of FK506 alone, FK506 and methylprednisolone, and FK506 and MTX." 0 0 . 0 0 0 W 0 0 m Y L 0- I I I R506 Only R506 t Pred. R506 t Mtx 8 ?l 0 0 0 8 RESULTS Engrafrment. Seventeen of the 18 patients in the FK506 group showed hematopoietic engraftment. The mean time to recovery of S00 neutrophils per microliter was 15.2 days (range, 8 to 23 days) in those patients who had received FK.506 alone or FK506 and methylprednisolone, and 21.7 days (range, 15 to 28 days) in patients who received FK506 and MTX. One patient who received FKS06 plus MTX died on day 23 after marrow transplantation with a granulocyte count of 423/pL. Pharmacokinetics. The mean clearance rates of FK506 on day 11 were similar for patients treated with FK506 by continuous intravenous infusion, alone or combined with methylprednisolone or MTX ( P = .61) (0.075 2 0.048 [5 patients], 0.055 f 0.023 [7 patients], and 0.063 2 0.032 L/ hrkg [ S patients], respectively; Fig 1A). The bioavailability of oral FK506 between weeks 4 and 8 was significantly different among the same three groups ( P = .003) and was the lowest in the group that received MTX (0.49 5 0.1 [5 patients], 0.27 2 0.12 [6 patients], and 0.16 It 0.08 [3 patients], respectively [value of l = 100% bioavailability]; Fig 1B). None of the four patients tested had an elevated level of MTX 24 hours after the dose requiring rescue with folinic acid. The mean clearance of methylprednisolone (0.5 mg/ kg) on day 11, in 7 patients tested, was 0.27 (50.11) L/min/ kg. Peak concentrations during the first hour after intravenous administration of methylprednisolone ranged from 166 to 278 ng/mL. Methylprednisolone concentrations then followed a typically linear decline. Cortisol was suppressed (< 10 ng/mL) in all patients except one. On oral prednisone, betweenweek 3 and 8, conversion to methylprednisolone was rapid. Prednisolone concentrations peaked at 183 to 676 ng/mL (mean, 379 2 169) between 1 to 4 hours after the oral dose of prednisone, and cortisol was usually fully sup- 0 0 0 0 FK506 Only FK506 t Pred. FK506 t Mtx fig 1. (AI Clearance of F 6 0 6 during continuous intravenous infusion. IBl Bioavailability of oral n<u)6. Group 1, F K W only; group 2, FKSO6 and prednisone; group3, FK506 MTX. Tho mean clearance and bioavailability for each group is indicated by IO). pressed. The mean clearance of prednisolone was 0.105 Ifr 0.44 Lhrikg. Adverse effects. Nephrotoxicity (increase of serum creatinine to 2X baseline or greater than 2 mg/dL) was the major adverse effect associated with GVHD prophylaxis with FK506-based immunosuppression. The cumulative incidence of nephrotoxicity during the first 100 days was 78% (Fig 2). Dialysis was required for four patients (22%). In three of these patients, dialysis occurred during preterminal acute events, including idiopathic pneumonitis, sepsis, or systemic Aspergillus infection. The fourth patient had a baseline GFR of 66 W m i n and had an increase in K 5 0 6 levels to 62 ng/mL during the first 7 days after marrow transplantation, temporally associated with the onset of VOD of the liver. To further assess renal function in patients on FK506based immunosuppression, GFR measurements were made before and during week 8 after marrow transplantation. All patients had GFR studies performed before transplant and 13 patients had GFR studies performed during week 8. All patients except one had a reduction inGFR (Fig 3). The mean GFR afte.r at least 8 weeks of FK506 was reduced to 56% ( P = .002 Wilcoxon sign rank test) of the baseline. Although nephrotoxicity was the most significant adverse effect, those nephrotoxic events not requiring dialysis, in From www.bloodjournal.org by guest on November 7, 2014. For personal use only. 3149 PREVENTION OF GVHD AFTER BMT WITH FK506 1.00 r 0.75 1 r 1 0.75 : p - - , 0 0 20 40 80 60 100 Fig 2. The cumulative incidence of nephrotoxicity in patients receiving FK506done or in combination with MTX or prednisone was 78%. A patient was defined as developing nephrotoxicity if there was a doubling of serum creatinine over baseline or an increase over 2 mg/dL at any time in the first 100 days aftermarrow transplantation (n = 18). general, occurred later in the period after transplantation, appeared more directly related to the toxic effects of FK506, and improved on dose reduction in all cases. Seven patients (39%) developed VOD as previously defined by McDonald et al.32Four patients had mild-moderate VODwith complete resolution of signs and symptoms. One patient with pre-existing mild liver disease before marrow transplantation developed severe VOD associated with significant ascites and a coagulopathy. Two patients who died before day 28 had clinical evidence of mildmoderate VOD but pulmonary complications secondary to systemic Aspergillus or toxicity from the conditioning regimen were found at autopsy. No association was observed between changes in bilirubin levels with FK506 dose adjustment. Other adverse effects were hypertension and hyperglycemia in nine and 10 patients, respectively. Sixpatients had hypercholesterolemia. All six patients developed hypercholesterolemia while on glucocorticoids and FK506 for prophylaxis or treatment of GVHD. One r 1 1 1 1 1 2 3 4 1 1 1 1 1 1 1 1 25 50 75 100 Days after Transplant Days after Transplant 300 0 1 1 , 1 1 1 5 6 7 8 9 10 11 121314151617 18 Patients Fig 3. Glomerular filtration rates for patients on FK506 before (01 and 8 weeks (0)after marrow transplantation.Thirteenpatientswere evaluable after marrow transplantation.The mean GFR was reduced to 56% of the pretransplant values ( P = .002). Fig 4. The cumulative incidence of acute GVHD (grades Il-IV) in patients receiving FK506 alone or in combination with MTX or prdnisone was 44% at 100 days (n = 18). of these also had hyperkalemia and required treatment with both fiudrocortisone acetate and gemfibrozil. These problems resolved after FK506 and prednisone were tapered. Neurologic adverse effects were noted in one patient who experienced delirium at the time FK506 whole blood levels were between 20 and 30 ng/mL. This resolved when the FK506 was held and other drugs were reduced in dose or discontinued. A burning discomfort in the extremities (hands and feet) or severe headaches during intravenous infusion occurred in 11 patients but improved or resolved after reducing the rateof the intravenous infusion or changing to oral FK506. Two patients required additional narcotic analgesia to control this discomfort. GVHD. The cumulative incidence of grades 11-IV acute GVHD was 44% (8/18; Fig 4). Skin GVHD occurred in six patients. In addition, six patients had GVHD of the gastrointestinal tract. Two patients were considered to have GVHD of the liver, but both of these patients also had moderatesevere hepatic VOD. Four of six patients receiving FK506 alone, one of seven patients receiving FK506 plus methylprednisolone, and three of five patients receiving FK506 plus MTX developed overall grades 11-IV GVHD. Six of the eight patients were treated with 2 mgkg of methylprednisolone for 2 to 3 weeks and then received tapered doses. Four of these patients had a complete response. Two of the eight patients had biopsy-proven GVHD of the upper GI tract only, manifested by anorexia and vomiting. One patient was treated with prednisone at 1 mgkg and the other with oral nonabsorbable beclomethasone (investigational drug). Both patients had responses and did not require second-line therapy. Only one patient received second-line treatment with ATG for an increasing serum bilirubin after FK506 had been discontinued. However, this patient also had VOD with ascites and a gram-negative bacteremia that likely contributed to the changes that led tothis intervention. Three of the eight patients who developed grades 11-IV GVHD were receiving IFN at the time of onset but there was no obvious correlation of administration of IFN to the development of acute GVHD. Nine patients in hematologic remission were evaluable for chronic GVHD (cGVHD). One patient was treated for subclinical cGVHD (positive lip and skin biopsies with an abnormal Schirmer's test) with FK506 and prednisone. Two From www.bloodjournal.org by guest on November 7, 2014. For personal use only. 3750 NASH ET AL transplant patients can developliver and gastrointestinal tract complications, all of which possibly could affect clearance or bioavailability. Drug interactions might also affect these parameters. Prednisolone inhibits FKS06 metabolism and another agent, such as FKS06, which is a substrate of cytochrome P-450 3A, cyclosporineA, can decrease the metabolism of prednis~lone.~'"Delays in MTX elimination have I I l I L been observed during the concomitant administration of ke0.25 6 toprofen and a macrolide-like antibiotic, Pristinarnycin."'.'' Clearance of FKS06 was similarinall threegroups.The 0 100 200 I 300 400 1 differences observed inbioavailability among the three Days after Transplant groups might have resulted from the exacerbation of the radiation-induced gastroenteritis by MTX. The range of valFig 5. The actuarial probability of nonrelapse mortality at l year ues for both clearance and bioavailability of FKS06 in our for the FK508 study group was 0.24, 1 year after the marrow transstudy were similar to results obtained after liver and small plantation. Tick marks indicate relapse or time of last contact for surviving patients. bowel transplantation. All studies have shown large interindividual ~ariability:~-~~ Because number the of patients studied here were small, the differencesobserved in the bioavailother patients developed cGVHDafter successfully tapering ability of FK506 among thethree groups will need to be off FKS06 at day 180 and were therefore treated with CSP confirmed. No major effect of FKS06 on clearance of methand prednisone as previously described.2h ylprednisolone or prednisolone wasfound, althoughthe Survival. Theactuarial probability of transplant-related clearance of methylprednisolone and prednisolone may have mortality during the first 100 days was 24% (Fig 5). Only been slightly decreased compared with results reported for 1 of 16 patients in the study (without myelodysplastic synhealthyindividuals.50,5' Therewasno apparenteffect of drome [MDS]) were in remission at the time of transplant. FKS06 in delaying the elimination of MTX, as determined Seven patients relapsed during the first year after transplant. by serumlevels 24 hours afterdosing.During thispilot The actuarial probability of disease-free survival was 39% study of FKS06, we wereattempting to maintain whole blood at 1 year after transplant. levelsbetween 2 and 60 ng/mL. More recently, for other studies, we have reduced the upper limit and increased the DISCUSSION lower limit of this range of whole bloodFKS06 levels. These pharmacokinetic results confirm that (1) althoughthe associPatients with advancedhematologic malignancies were ation betweenwholebloodFKS06levels and toxicity or selected for this study of acute GVHD prevention because acute GVHD is currently unclear, the high degree of interinthe efficacy and safety of FKS06 as an immunosuppressive dividual variability in clearance and bioavailability resulting agent after marrow transplantation was unknown. If these from multiple factors, requires routine monitoring and adpatients with a high risk of relapse had a higher incidence justments of dose; and (2) FKS06 does not have any signifiof acute GVHD asa result ofusing this new agentthan what cant interactions onotherimportantimmunosuppressive otherwise might have been expected, the overall survivalof agents now used after marrow transplantation. the group mightnot have been affected because of the graftThe major adverse effect associated with the administraversus-leukemia During this period, patients with tion of FKS06 was nephrotoxicity. Renal tubular celldamage advanced hematologicmalignancies received more intensive and glomerular thrombosis have been associated with FKS06 conditioning regimens at this center, either with higher doses nephrotoxicity." FKS06 has been reported to be cytotoxic of TB1 (1,575 cGy) or intensified chemotherapy (combinafor tubular cells in vitro,inducingultrastructural changes tion of busulfan andcyclophosphamide with TBI).More and delayed regeneration. Moreover, release of endothelin intensified conditioning regimens,especially with intensified from renal tubular cells may perturb renal hemodynamics, TBI, have been associated with an increased incidence of decreasing GFR and renal plasma flow and increasing renal acute GVHD.2*38339 This may occur becauseof a potentiating vascular Sodium depletion experimental in an effect of TB1 on acute GVHD. Another reason for the inrat model potentiates FKS06 nephrotoxicity." The incidence creased incidence of acute GVHD might be an inability to of severe nephrotoxicity requiring hemodialysis was similar administer effective dosesof immunosuppressive agents beto what has been previouslyreported after marrowtranscause of the increased regimen-relatedtoxicity. The inciplantationwithCSP-basedregimens of GVHDprophydence of acute GVHD reported in this study is comparable laxis.sh In thefour patients of thisstudy of FKS06 who to what has been reported in previous studies ofpatients requiredhemodialysis,nephrotoxicity was associatedwith receiving conditioning regimens of higher in tens it^.^*,^^ In hepatic VOD or serious infections. Although it is likely that this study, an increased risk of acute GVHD was not obFKS06was contributory, the limitedobservations in this served with I F N administration!" study would confirm what has been previously reported with FKS06 is a highly lipophilic macrolide with a large volCSP, thatin patients earlyafter marrow transplantation, other ume ofdistribution. The drug is primarily eliminated by complicationssuchasVOD, sepsis, hypotension,andthe hepatic metabolism(P-4503A),with less than 1% of an use ofAmphotericin B more closelycorrelate with the develintravenous or an oral dose appearing in the urine. Marrow 3 c OP' I From www.bloodjournal.org by guest on November 7, 2014. For personal use only. 3751 PREVENTION OF GVHD AFTER BMT WITH FK506 opment of acute renal failure requiring hem~dialysis.~~ After liver transplantation, nephrotoxicity observed in the FK506 group was also described as the major adverse effect, OCcurring in 37% to 54% of patients, similar to the incidence observed in patients treated with CSP.57-59 Because both the immunosuppressive and nephrotoxic effects of FK506 may be linked to the ability of the FK506-binding protein-12 complex to inhibit the phosphatase activity of calcineurin, a degree of nephrotoxicity may be unavoidable to achieve adequate immunosuppression.@’ The incidence of VOD has previously been determined to be 54% and severe VOD was seen in 15% of patients after marrow tran~plantation.~~ The incidence of VOD in this study of FK506 in patients who were at higher risk of developing this complication because of the higher-dose regimen of cytoreductive therapy is comparable to the previous experience. Hypertension and hyperglycemia were common but manageable adverse effects. After marrow transplantation with CSP for GVHD prophylaxis, a 60% incidence of hypertension was reported, similar to what was obtained in this study of FK506.61 In a prospective randomized trial comparing FK506 to CSP after liver transplantation, hypertension was less frequent in the group receiving FK506.6*Hyperglycemia has been observed in 17% to 20% of patients treated with FK506 after liver and kidney tran~plantation.~~’~~ Preclinical studies in rats, dogs, and primates have indicated that one of the mechanisms for the development of hyperglycemia was a reduction in insulin secretion during treatment.”@ Seizures, delirium, dysarthria, or coma occurred in 8.4% of liver transplant patients treated with FK506.57These complications were associated with toxic FK506 levels and responded to dose reduction in all but one case. The spectrum of FK506-related complications observed after marrow transplantation is similar to that observed after solid organ transplantation. FK506-based immunosuppression after marrow transplantation has an acceptable safety profile and has immunosuppressive activity that appears to be effective for prophylaxis of acute GVHD. No significant interactions were observed between FK506, MTX, or prednisone that affected clearance, although because bioavailability of oral FK506 in patients receiving MTX may be reduced, blood levels should be carefully monitored. In another recent phase I1 study of FK506 alone for GVHD prophylaxis after marrow transplantation from HLA-matched siblings, the incidence of grades 11-IV acute GVHD in 27 patients was 41%.67Based on phase I1 clinical studies in marrow transplantation and on the preclinical study of GVHD in dogs showing that FK506 in combination with MTX significantly decreased the incidence of acute GVHD compared with FK506 alone, further studies are indicated to compare FK506 and MTX with CSP and MTX in patients receiving marrow grafts from HLA-matched siblings. REFERENCES 1. StorbR, Thomas ED: Graft-versus-host disease in dog and man: The Seattle experience. Immunol Rev 88:215, 1985 2. Nash RA, Pepe MS, Storb R, Longton G, Pettinger M, Anasetti C, Appelbaum FR, Bowden RA, Deeg HJ, Doney K, Martin PJ, Sullivan KM, Sanders J, Witherspoon RP: Acute graft-versus-host disease: Analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate. Blood 80:1838, 1992 3. Storb R, Deeg HJ, Farewell V, Doney K, Appelbaum F, Beatty P, Bensinger W, Buckner CD, Clift R, Hansen J, Hill R, Longton G, Lum L, Martin P, McGuffin R, Sanders J, Singer J, Stewart P, Sullivan K, Witherspoon R, Thomas ED: Marrow transplantation for severe aplastic anemia: Methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 68: 119, 1986 4. Storb R, Deeg HJ, Whitehead J, Appelbaum FR, Beatty P, Bensinger W, Buckner CD, Clift R, Doney K, Farewell V, Hansen J, Hill R, Lum L, Martin P, McGuffin R, Sanders J, Stewart P, Sullivan K, Witherspoon R, Yee G, Thomas ED: Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 314:729, 1986 5 . 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